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Structure of 89466-08-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 805 - 811
4
[ 89466-08-0 ]
[ 129946-88-9 ]
[ 444-30-4 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 14, p. 4300 - 4302
5
[ 589-87-7 ]
[ 89466-08-0 ]
[ 21849-89-8 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium phosphate In 1,4-dioxane; water at 100℃;
Intermediate 27 : 4'-Bromo-2-biphenylol1-Bromo-4-iodobenzene (Aldrich, 2 g, 7.07 mmol), (2-hydroxyphenyl)boronic acid (Aldrich, 1.073 g, 7.78 mmol) , Pd(Ph3P) (0.204 g, 0.177 mmol) were dissolved in 1 ,4-dioxane (30 ml_) and water (10 ml_), K3P04 (2.251 g, 10.60 mmol) was added. The reaction mixture was stirred at 100 °C overnight. Solvents were removed under reduced pressure and DCM was added, mixture was washed with water, dried over anhydrous sodium sulfate. Then solvent was removed under reduced pressure to give the title product 4'-bromo-2-biphenylol (1.85 g, 6.54 mmol, 92 percent yield) as brown oil. LCMS: (M+H)+ = 247-249 ; Rt = 3.52 min.
Reference：
[1] Patent: WO2012/119978, 2012, A1, . Location in patent: Page/Page column 55
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 17, p. 8068 - 8081
[3] Patent: US2010/81643, 2010, A1, . Location in patent: Page/Page column 44
[4] Patent: WO2010/47982, 2010, A1, . Location in patent: Page/Page column 88
[5] Patent: WO2010/51176, 2010, A1, . Location in patent: Page/Page column 82
[6] Patent: WO2010/51206, 2010, A1, . Location in patent: Page/Page column 82-83
[7] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 9040 - 9052
Under nitrogen, 1.5 kg of 2-methoxyphenylboronic acid was added to a 30 L glass reactor,18 liters of anisole and 1.56 kg of acetyl chloride. After the addition was completed, the reaction mixture was cooled to -10 to 0 ° C and stirred for 1 hour. Begin adding 133 g of anhydrous aluminum trichloride in batches. After the addition is completed, the temperature is naturally raised to room temperature, and the mixture is kept under stirring until TLC shows that the reaction of raw materials is complete. This process takes about 8 to 10 hours. During this process, the solid of the reaction mixture gradually dissolves, followed by gradual solid precipitation. Add 5M potassium hydroxide aqueous solution quench, adjust PH = 11 ~ 12 so far. At this point the organic layer is separated and discarded. Aqueous layer was added 6M aqueous hydrochloric acid to adjust the PH = 2 ~ 3, 12 liters of ethyl acetate extraction twice, the organic layer was combined, washed with saturated brine, the organic layer spin dry, beating with acetone / n-heptane afforded o-hydroxybenzene boronic acid 1.06 kg, 77percent yield, HPLCAmount: 98.6percent.
4-(3,4-diethoxyphenyl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
tris-(dibenzylideneacetone)dipalladium(0);
Example 145 4-(3,4-diethoxyphenyl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-hydroxyphenyl)boronic acid (17.2 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (5.1 mg) was obtained. HPLC (220 nm) purity 92% (retention time 1.89 min) MS (ESI+, m/e) 511 (M+H)
4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
tris-(dibenzylideneacetone)dipalladium(0);
Example 177 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-hydroxyphenyl)boronic acid (17.2 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (10.6 mg) was obtained. HPLC (220 nm) purity 81% (retention time 1.86 min) MS (ESI+, m/e) 465 (M+H)
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 10h;
To a round bottom flask containing (2-hydroxyphenyl)boronic acid (1.37 g, 9.9 mmol) in 1,4-dioxane : water (8:1, 40 ml) was added methyl 6-chloronicotinate (1.71 g, 10.0 mmol), potassium carbonate (4.14g, 30.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.3g, 0.26 mmol) and the resulting mixture stirred at 80 C. for 10 h, then stood at r.t. for 72 h. The solution was acidifed to pH 1 with aqueous 2 N HCl and concentrated in vacuo to a volume of approximately 5 ml. This solution was then partitioned between saturated sodium hydrogen carbonate (30 ml) and dichloromethane:methanol (95:5, 150 ml). The layers were separated and the aqueous layer extracted with dichloromethane (50 ml). The organic layers were combined and dried with anhydrous MgSO4, filtered and concentrated to afford a yellow solid. The solid was recrystallised from ethyl acetate/methanol to give the title compound as a yellow solid (1.14g) (50%). 1H NMR (400 MHz, CDCl3) ppm 9.16 (1 H, s), 8.46-8.40 (1 H, m), 8.02-7.96 (1 H, m ), 7.86-7.80 (1 H, m), 7.39-7.33 (1 H, m), 7.10-7.04 (1 H, m), 6.96-6.90 (1 H, m), 4.00 (3 H, s). LRMS: AP m/z 230 [M+H]+.
With sodium carbonate In water; toluene for 0.25h; Heating / reflux;
26-A
2,4-Dichloroquinoline (0.500 g, 2.525 mmol), 2-hydroxyphenylboronic acid (0.332 g, 2.405 mmol), sodium carbonate (0.510 g, 4.810 mmol) and Pd(PPh3)4 (0.139 g, 120 mmol) were added to a degassed mixture of toluene (5 mL) and water (2 mL), and the mixture was heated for 15 hours. After cooling, water (100 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography (dichloromethane) to give the title compound (0.322 g, 50%).LC-MS (LCT2) m/z 256 [M+H+], R, 5.84 minutes.
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃;
Intermediate 27 : 4'-Bromo-2-biphenylol1-Bromo-4-iodobenzene (Aldrich, 2 g, 7.07 mmol), (2-hydroxyphenyl)boronic acid (Aldrich, 1.073 g, 7.78 mmol) , Pd(Ph3P) (0.204 g, 0.177 mmol) were dissolved in 1 ,4-dioxane (30 ml_) and water (10 ml_), K3P04 (2.251 g, 10.60 mmol) was added. The reaction mixture was stirred at 100 C overnight. Solvents were removed under reduced pressure and DCM was added, mixture was washed with water, dried over anhydrous sodium sulfate. Then solvent was removed under reduced pressure to give the title product 4'-bromo-2-biphenylol (1.85 g, 6.54 mmol, 92 % yield) as brown oil. LCMS: (M+H)+ = 247-249 ; Rt = 3.52 min.
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 1h;
Step A 4'-bromobiphenyl-2-ol. Potassium phosphate (2 M in water) (5.5 ml, 10.9 mmol) and Pd(PPh3)4 (209 mg, 0.18 mmol) were added to a solution of 1-bromo-4-iodobenzene (2.05 g, 7.25 mmol), and 2-hydroxybenzeneboronic acid (1 g, 7.25 mmol) in dioxane (50 mL). The reaction was heated at 100 C. for 1 h. Volatiles were removed and the residue was purified by chromatography over silica eluting with 0-50% EtOAc/hexane to afford the desired product as a light yellow oil.
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1h;
Potassium phosphate (2 M in water) (5.5 ml, 10.9 mmol) and Pd(PPh3) 4 (209 mg, 0.18 mmol) were added to a solution of l-bromo-4-iodobenzene (2.05 g, 7.25 mmol), and 2-hydroxybenzeneboronic acid (1 g, 7.25 mmol) in dioxane (50 mL). The reaction was heated at 1000C for 1 h. Volatiles were removed and the residue was purified by chromatography over silica eluting with 0-50% EtOAc/hexane to afford the desired product as a light yellow oil.
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1h;
Potassium phosphate (2 M in water) (5.5 ml, 10.9 mmol) and Pd(PPh3) 4 (209 mg, 0.18 mmol) were added to a solution of 1 -bromo-4-iodobenzene (2.05 g, 7.25 mmol), and 2-hydroxybenzeneboronic acid (1 g, 7.25 mmol) in dioxane (50 mL). The reaction was heated at 1000C for 1 h. Volatiles were removed and the residue was purified by chromatography over silica eluting with 0-50% EtOAc/hexane to afford the desired product as a light yellow oil.
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1h;
Potassium phosphate (2 M in water) (5.5 ml, 10.9 mmol) and Pd(PPh3) 4 (209 mg, 0.18 mmol) were added to a solution of l-bromo-4-iodobenzene (2.05 g, 7.25 mmol), and 2-hydroxybenzeneboronic acid (1 g, 7.25 mmol) in dioxane (50 mL). The reaction was heated at 1000C for 1 h. Volatiles were removed and the residue was purified by chromatography over silica eluting with 0-50% EtOAc/hexane to afford the desired product as a light yellow oil.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2h;Reflux;
(Example 38-1) At room temperature, to a tetrahydrofuran solution (60 ml) of 5-bromo-3-nitropyridine-2-carbonitrile (6.00 g) was added a tetrahydrofuran solution (1 M, 52.8 ml) of tetrabutylammonium fluoride, followed by stirring for 1 hour. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford <strong>[886373-28-0]5-bromo-3-fluoropyridine-2-carbonitrile</strong>. To a mixed solvent solution of this in 1,2-dimethoxyethane (120 ml) and water (30 ml) were added 2-hydroxyphenylboronic acid (4.37 g), sodium carbonate (8.39 g) and tetrakis(triphenylphosphine)palladium (1.52 g), followed by stirring under heating at reflux for 2 hours. The reaction solution was brought back to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 3-fluoro-5-(2-hydroxyphenyl)pyridine-2-carbonitrile (2.73 g). 1H NMR (400 MHz, CDCl3) delta: 5.12 (br s, 1H), 6.91 (d, 1H, J = 8.0 Hz), 7.00 (t, 1H, J = 8.0 Hz), 7.27-7.39 (m, 2H), 7.85 (dd, 1H, J = 11.2, 1.6 Hz), 8.77 (t, 1H, J = 1.6 Hz).
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere;
General procedure: The 2-bromoarylcarboxaldehyde (1 mmol), 2-hydroxyphenylboronic acid (1 mmol), K2CO3 (1 mmol.), PPh3 (0.25 mmol) were taken in a two-necked round bottomed flask and flushed with nitrogen gas. Then 3 mL of DMF was added and degassed with N2. The catalyst Pd(OAc)2 (5 mol%) was added to the reaction mixture and heated at 90 ?C for 4 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) and hexane/EtOAc as eluent.
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 90℃; for 8h;Inert atmosphere;
General procedure: The 2-bromoarylcarboxaldehyde (1 mmol), 2-hydroxyphenylboronic acid (1 mmol), K2CO3 (1 mmol.), PPh3 (0.25 mmol) were taken in a two-necked round bottomed flask and flushed with nitrogen gas. Then 3 mL of DMF was added and degassed with N2. The catalyst Pd(OAc)2 (5 mol%) was added to the reaction mixture and heated at 90 ?C for 4 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) and hexane/EtOAc as eluent.
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere;
General procedure: The 2-bromoarylcarboxaldehyde (1 mmol), 2-hydroxyphenylboronic acid (1 mmol), K2CO3 (1 mmol.), PPh3 (0.25 mmol) were taken in a two-necked round bottomed flask and flushed with nitrogen gas. Then 3 mL of DMF was added and degassed with N2. The catalyst Pd(OAc)2 (5 mol%) was added to the reaction mixture and heated at 90 ?C for 4 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) and hexane/EtOAc as eluent.
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere;
General procedure: The 2-bromoarylcarboxaldehyde (1 mmol), 2-hydroxyphenylboronic acid (1 mmol), K2CO3 (1 mmol.), PPh3 (0.25 mmol) were taken in a two-necked round bottomed flask and flushed with nitrogen gas. Then 3 mL of DMF was added and degassed with N2. The catalyst Pd(OAc)2 (5 molpercent) was added to the reaction mixture and heated at 90 ?C for 4 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) and hexane/EtOAc as eluent.
With palladium diacetate; potassium carbonate; triphenylphosphine In N,N-dimethyl-formamide at 90℃; for 4h; Inert atmosphere;
General procedure for the one-pot synthesis of benzo[c]chromen-6-ones:
General procedure: The 2-bromoarylcarboxaldehyde (1 mmol), 2-hydroxyphenylboronic acid (1 mmol), K2CO3 (1 mmol.), PPh3 (0.25 mmol) were taken in a two-necked round bottomed flask and flushed with nitrogen gas. Then 3 mL of DMF was added and degassed with N2. The catalyst Pd(OAc)2 (5 mol%) was added to the reaction mixture and heated at 90 ∘C for 4 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) and hexane/EtOAc as eluent.
79%
With palladium diacetate; potassium carbonate; triphenylphosphine In N,N-dimethyl-formamide at 90℃; Inert atmosphere;
1.1 Step 1) 8-fluoro-6H-benzo[c]chromen-6-one
Add 2-bromo-5-fluoro-benzaldehyde (1mmol), 2-hydroxyphenylboronic acid (1mmol), K2CO3 (1mmol.), and PPh3 (0.25mmol) and Pd(OAc)2 (5mol%) to the reaction flask , 3mL DMF was added under nitrogen protection, the mixture was stirred at 90°C under nitrogen protection, the reaction progress was detected by TLC, after the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (20mL) and extracted with ethyl acetate (20mL X 3), The ethyl acetate phase was collected and dried over anhydrous sodium sulfate. After concentration, the silica gel column was purified and separated (yield: 79%)
With palladium diacetate; potassium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 90℃; for 4h;Inert atmosphere;
General procedure: The 2-bromoarylcarboxaldehyde (1 mmol), 2-hydroxyphenylboronic acid (1 mmol), K2CO3 (1 mmol.), PPh3 (0.25 mmol) were taken in a two-necked round bottomed flask and flushed with nitrogen gas. Then 3 mL of DMF was added and degassed with N2. The catalyst Pd(OAc)2 (5 mol%) was added to the reaction mixture and heated at 90 ?C for 4 h. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using silica gel (60-120 mesh) and hexane/EtOAc as eluent.
In diethyl ether; at 20℃; for 18h;Inert atmosphere; Sealed tube;
General procedure: A non-flame-dried round-bottom flask was charged with boronic acid, pinacol (2 equiv), and Et2O (0.1 M) and the mixture allowed to stir at r.t. for 18 h. The solvent was removed in vacuo and the crude was filtered through a plug of silica eluting with Et2O.
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); potassium bromide; In 1,4-dioxane; at 85℃;Inert atmosphere;
General procedure: A stirred mixture of <strong>[51628-12-7]4-iodophenylacetonitrile</strong> (35), arylboronic acid (36-45) (1.1 equiv), Pd(PPh3)4 (0.03 equiv), KBr (1.1 equiv), and K3PO4 (2.5 equiv) in dioxane (5 mL/mmol) was purged with N2 for10 min at room temperature and then stirred overnight at 85 C under N2. The mixture was diluted with water and extracted with AcOEt. The organic phase was washed three times with water, dried (Na2SO4), and evaporated under vacuum. The residue was chromatographedon silica gel.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; for 2h;Reflux;
A mixture of <strong>[1150566-27-0]ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate</strong> (200.0 mg, 0.89 mmol), 2-hydroxyphenylboronic acid (183.0 mg, 1.33 mmol) Cs2CO3 (342.0 mg, 1.77 mmol), and Pd(PPh3)4 (102.0 mg, 0.09 mmol) was taken up in dioxane (4 mL) and refluxed for 2 h. After cooling to room temp, the reaction was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude material was purified by vacuum distillation to afford ethyl 6-(2-hydroxyphenyl)imidazo[1,2-b]pyridazine-3-carboxylate (120.0 mg, 47.8%). MS (ESI) calcd for C15H13N3O3: 283.1
47.8%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; for 2h;Reflux;
A mixture of <strong>[1150566-27-0]ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate</strong> (200.0 mg, 0.89 mmol), 2-hydroxyphenylboronic acid (183.0 mg, 1.33 mmol) Cs2CO3 (342.0 mg, 1.77 mmol), and Pd(PPh3)4 (102.0 mg, 0.09 mmol) was taken up in dioxane (4 mL) and refluxed for 2 h. After cooling to room temp, the reaction was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude material was purified by vacuum distillation to afford ethyl 6-(2-hydroxyphenyl)imidazo[1,2-b]pyridazine-3-carboxylate (120.0 mg, 47.8%). MS (ESI) calcd for C15H13N3O3: 283.1
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; water; toluene; at 100℃; for 1h;Microwave irradiation;
General procedure: AG10 vial in a Microwave 300 vessel was charged with 6-bromopyridinecarboxaldehyde,or <strong>[122918-25-6]6-bromopyridinecarbonitrile</strong>(1 eq), boronic acid (2 eq),Na2CO3 (4 eq), and Pd(PPh3)2Cl2(10 mol%). Toluene/EtOH/water/ (2/1/1 mL) were next added. The resulting mixturewas irradiated using the closed vessel mode at 100C for 60 min. The mixture wasthen extracted with dichloromethane, washed with a saturated solution of NaHCO3,dried over MgSO4, and concentrated by rota-evaporation under vacuum.The crude product was purified by flash chromatography, with a pentane /AcOEt (9/1to 7/3) as the eluent.
2-(2-hydroxyphenyl)thiazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 20 - 150℃; for 0.833333h;Sealed tube; Inert atmosphere;
A microwavevial was charged with <strong>[848501-90-6]2-bromo-4-cyanothiazole</strong> (1.06 mmol), 2-(hydroxyphenyl)boronic acid (1.38 mmol), and Pd(PPh3)4(0.0529 mmol) (Scheme 2). The vial was sealed and flushedwith argon for 5 min. Dimethoxyethane (8 mL) and a 2 Mpotassium carbonate solution (1.06 mL, 2.12 mmol) wereadded through the septum, and the reaction mixture was stirredat room temperature for an additional 5 min and then heated to150 C for 45 min using a microwave reactor. The reactionmixture was cooled to room temperature and diluted with anEtOAc/H2O mixture (2:1, 30 mL). The aqueous layer wasextracted with EtOAc (2 × 30 mL). The organic layers werecombined, washed with brine, and dried over Na2SO4. Thesolvent was removed in vacuo, and the resulting residue waspurified by flash column chromatography (1:5 EtOAc/pentane)to yield a pale yellow solid (104 mg, 49%): mp 169-172 C;1H NMR (500 MHz, DMSO-d6) delta 11.42 (s, 1H), 8.84 (s, 1H),8.17 (dd, J = 7.9, 1.7 Hz, 1H), 7.39 (ddd, J = 8.6, 7.2, 1.7 Hz,1H), 7.07 (dd, J = 8.3, 1.2 Hz, 1H), 7.00 (td, J = 7.8, 1.1 Hz,1H); 13C NMR (126 MHz, DMSO-d6) delta 164.13, 155.12,133.20, 132.06, 127.36, 124.01, 119.60, 118.24, 116.30, 114.91.
4,4,5,5-tetramethyl-2-(trans-2-phenylcyclopropyl)-1,3-dioxolane[ No CAS ]
2-(6-amino-5-((1R,2R)-2-phenylcyclopropyl)pyridazin-3-yl)phenoL[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4-bromo-6-chloropyridazin-3 -amine (100 mg, 0.480 mmol), 4,4,5 ,5-tetramethyl-2-(trans-2-phenylcyclopropyl)-1,3-dioxolane (0.177 g, 0.720 mmol) (contaminated with (E)-4,4,5,5-tetramethyl-2-styryl- 1,3 ,2-dioxaborolane), tetrakis(triphenylphosphine)palladium(0) (0.056 g, 0.048 mrnol), potassium carbonate (0.1989 g, 1.4391 mmol), 1 ,4-dioxane (2 mL) and water (0.2 mL) were charged in a vial. The headspace was flushed with nitrogen and the reaction mixture was degassed using 4 cycles of vacuum and nitrogen refilling. The reaction was heated at 100 Covernight then methanesulfonato(2-dicyclohexylphosphino-2?,4?,6?-tri-i-propyl- 1,1 biphenyl)(2l amino-1,1?-biphenyl-2-yl)palladium(II) (0.020 g, 0.024 mmol) and (2-hydroxyphenyl)boronic acid (0.132 g, 0.959 mmol) were added. The headspace was flushed with nitrogen and the reaction was heated to 100 C for 90 mm. After the reaction was cooled to room temperature, the desired product was purified by silica gel chromatography (eluting with hexanes/ ethyl acetate)and by reverse phase preparative HPLC (eluting with water acetonitrile 0.1% trifluoroacetic acid). The stilbene side product could not be separated from the title compound.
2-(6-amino-5-benzylpyridazin-3-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1%
2-benzyl-4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolane (188 mg, 864 tmol), 4-bromo-6-chloropyridazin-3 -amine (150 mg, 0.720 mmol), tetrakis(triphenylphosphine)palladium(0) (83.15 mg, 71.96 iimol), potassium carbonate (298 mg, 2.16 mmol), 1 ,4-dioxane (3 mL) and water (0.2 mL) were charged in a vial. The headspace was flushed with nitrogen and the reaction mixture was degassed using 4 cycles of vacuum and nitrogen refilling. The reaction was heated at 100 C overnight. Next morning, extra tetrakis(triphenylphosphine)palladium(0) (83.15 mg,71.96 iimol) was added. After 2 d, extra 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (188.3 mg, 863.5 jimol) was added and the reaction was heated for 4 h, then (2- hydroxyphenyl)boronic acid (0.198 g, 1.44 mmol) and methanesulfonato(2- dicyclohexylphosphino-2?,4?,6?-tri-i-propyl- 1,1 ?-biphenyl)(2?-amino- 1,1 ?-biphenyl-2- yl)palladium(II) (61 mg, 0.072 mmol) were added. The headspace was flushed with nitrogen andthe reaction is heated to 100 C. After 5 h the reaction is cooled to room temperature, filteredand purified by silica gel chromatography (eluting with hexane ethyl acetate). The residue waspurified by reverse phase preparative HPLC to give the title compound as a tan solid (2 mg; 1%yield). LCMS M/Z (M+H) 278.
(E)-2-(6-amino-5-(3-phenylprop-1-en-1-yl)pyridazin-3-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
(E)-(3-phenylprop-1-en-1-yl)boronic acid (0.466 g, 2.88 mmol), 4-bromo-6-chloropyridazin-3- amine (400 mg, 1.92 mmol), tetrakis(triphenylphosphine)palladium(0) (0.111 g, 0.096 mmol),potassium carbonate (1.06 g, 7.68 mmol), 1 ,4-dioxane (3 mL) and water (0.15 mL) were chargedin a vial. The headspace was flushed with nitrogen and the reaction mixture was degassed using 3 cycles of vacuum and nitrogen refilling. The reaction was heated at 90 C. After 3 h, methanesulfonato(2-dicyclohexylphosphino-2,4?,6-tri-i-propyl- 1,1 ?-biphenyl)(2?-amino- 1,1?- biphenyl-2-yl)palladium(II) (0.08 1 g, 0.096 mmol) and (2-hydroxyphenyl)boronic acid (0.529 g,3.84 mmol) were added. The headspace was flushed with nitrogen and the reaction was heated to90 C. After 2 h the reaction was cooled to room temperature and purified by silica gelchromatography (eluting with methylene chloride methanol). The title compound was obtain asa tan solid (34 mg; 6% yield). LCMS M/Z (M+H) 304.
3-amino-6-(2-hydroxyphenyl)-N-(trans-2-phenylcyclopropyl)pyridazine-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3%
<strong>[446273-59-2]4-bromo-6-chloropyridazin-3-amine</strong> (300 mg, 1.44 mmol), trans-2-phenylcyclopropanamine(0.767 g, 5.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.144 mmol) and dimethylformamide (10 mL) were charged in a disposable reaction tube. The headspace was flushed with nitrogen and the reaction mixture was degassed using 3 cycles of vacuum and nitrogen refilling. The reaction was heated at 85 C under a continuous flow of carbon monoxide (bubbling in the reaction mixture) and after 90 mm the reaction was cooled to room temperature.The headspace was flushed with nitrogen, then (2-hydroxyphenyl)boronic acid (0.397 g, 2.88 mmol), methanesulfonato(2-dicyclohexylphosphino-2,4,6?-tri-i-propyl- 1,1 ?-biphenyl)(2?-amino- 1,1?-biphenyl-2-yl)palladium(II) (60 mg) and water (0.3 mL) were added. The reaction mixture was degassed using 3 cycles of vacuum and nitrogen refilling and heated at 100 C. After 3 h, an aqueous solution of ammonium chloride was added and the desired product was extracted withethyl acetate (repeated three times). The combined organic layers were washed with water, dried with sodium sulfate, filtered and concentrated to dryness under vacuum. The desired product was purified by reverse phase preparative HPLC (eluting with acetonitrile water 0.1% trifluoroacetic acid) to give the title compound as a light yellow solid (16 mg, 3% yield). ?H NMR (400 MHz, DMSO-d6) 13.00 (s, 1H), 9.24 (d, J = 3.91 Hz, 1H), 8.36 (s, 1H), 7.89 (dd, J= 1.59, 7.93 Hz, 1H), 7.36 (br. s, 2H), 7.26 - 7.32 (m, 3H), 7.16 - 7.21 (m, 3H), 6.93 - 6.99 (m,2H), 3.05 (sxt, J = 4.00 Hz, 1H), 2.13 - 2.21 (m, 1H), 1.34 - 1.42 (m, 1H), 1.25 - 1.33 (m, 1H). LCMS MIZ (M+H) 347.
With potassium fluoride; palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In tetrahydrofuran; water; at 20℃; for 1.5h;Inert atmosphere;
B-2 (2.17 g, 10.0 mmol) and 2-hydroxybenzene boronic acid (1 .38 g, 10.0 mmol) were dissolved in 10 mL of THF. To the solution was added potassium fluoride (1.74 g, 30.0 mmol) dissolved in 5 mL of water, and the mixture was evacuated and purged with Argon gas. Then, 'Betaupsilon3Rho-EtaBetaRho4 (290 mg, 1.00 mmol) and Pd(OAc)2 (225 mg, 1.00 mmol) were added to the mixture, and the mixture was stirred at room temperature for 1 .5 h. The reaction mixture was dried with MgS04, filtrated over Celite and washed with ethyl acetate. The crude was purified by column chromatography on silica gel eluting with a mixed solvent of heptane and ethyl acetate (3:1 ) to yield 2.27 g (96%) of B-3 as a slightly yellow solid. It was used for next reaction without purification.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 6h;Schlenk technique;
accurately weighed 2,3-dibromobenzo [fo] thiophene (683 mg, 2.34 mmol), 2-light benzene phenylboronic acid (484 mg, 3.5(1 · 29 g, 9.36 mmol), tetrakis (triphenylphosphine) palladium (0.05 equivalent), 1,4-dioxane Hexahedral / water (volume ratio 4: 1), placed in a 90 C oil bath for 6 hours. After completion of the reaction, the solvent was removed under reduced pressure, and silica gel column separation, petroleum ether / ethyl acetate was used as the eluent to give 2- (3-bromobenzothiazol-2-yl) phenol 3a in 84% yield.
With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; potassium carbonate; In ethanol; toluene; at 50℃; for 1h;
(1) 10 mmol of the starting material 1a and 10 mmol of the starting material 1b were dissolved in 50 ml of a toluene/ethanol mixed solution (V ethanol: V toluene = 20%), and 20 mmol of potassium carbonate and 0.5 mmol of tetrabutylammonium bromide 0.02 mmol were added under stirring. Triphenylphosphine palladium, the reaction temperature is 50 C, the reaction time is 1 hour, the completion of the reaction of the starting materials, extraction with 50 ml of toluene, 100 ml of water to neutral, 10 g of anhydrous sodium sulfate drying for 30 min, then distilled under reduced pressure at 45 C ( The pressure -0.06 to -0.08 MPa) is concentrated to a remaining small amount of solvent and then recrystallized to obtain Intermediate 11, and the reaction equation is as follows:
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In methanol; water; toluene;Inert atmosphere;
General procedure: <strong>[405224-23-9]5-bromo-2-chloronicotinonitrile</strong> (5, 2.16 g, 10 mmol), aromatic boronic acid (10 mmol), (PPh3)2PdCl2 (175 mg, 0.25 mmol), Na2CO3 (2.12 g, 20 mmol) were dissolved in a mixed solvent (22 mL, toluene: ethanol: water = 10: 10: 2). Nitrogen gas was bubbled through the reaction mixture for 5 min, and then the mixture was heated to 60C under inert atmosphere for 6 h. The mixture was filtered and the filtrate was concentrated under vacuum. The crude product was extracted with ethyl acetate and the organic layer was concentrated, then the solid was washed with ethyl acetate and petroleum ether to give compounds 6.
5-(2-hydroxyphenyl)thiophene-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
183 mg
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 110℃; for 4h;Inert atmosphere;
248 mg of <strong>[100523-84-0]5-bromothiophene-3-carboxylic acid</strong>, 251 mg of 2-hydroxyphenylboronic acid,101 mg of tetrakis (triphenylphosphine) palladium and 340 mg of anhydrous potassium carbonate were added to a tolueneEthanol / water (18/1/1) mixed solvent at room temperature under argon atmosphere at 110 C. for 4 hoursFollowed by stirring. After completion of the reaction, the reaction was stopped with 10% hydrochloric acid and the reaction product was extracted with ethyl acetate.After drying the organic layer with magnesium sulfate, only the organic layer was recovered by filtration. An evaporatorAfter removal of the organic solvent with silica gel column chromatography (developing solvent: methylene chlorideTylene / methanol = 15/1 to 10/1) to give 183 mg of the title compound.
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In 1,4-dioxane; water; at 70℃;Inert atmosphere;
A 5ml microwave vial containing a Teflon stirred bar was charged with the commercial <strong>[148493-37-2]2,6-dichloro-3-iodopyridine</strong> (2.0 g, 7.16 mmol, 1 eq.), the 2-hydroxyphenyl boronic acid (1.08 g, 7.87 mmol, 1.1 eq.), K2C03 (2,97 g, 21.47 mmol, 3 eq.) followed by the addition of PdCl2(dppf) (262 mg, 0.36 mmol, 0.05 eq). A mixture of l,4-dioxane/H20: 4/1 (50 mL) was then introduced, the vessel was evacuated and backfilled with nitrogen (this process was repeated a total of 3 times). The reaction mixture was then capped properly and placed in a preheated oil bath at 70C until complete conversion of the starting material was detected (approximatively 16 hours). After evaporation of the volatiles the residue was diluted with EtOAc, successively washed with brine and water. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using EtO Ac/heptane: 1/2 to afford the expected 2-(2,6-dichloropyridin-3-yl)phenol as a white solid (1.52 g, 88%).H-NMR (400 MHz, DMSO-d6): d 9.73 (s, 1H), 7.85 (d, J= 7.7 Hz, 1H), 7.60 (d, J= 8.2 Hz, 1H), 7.26 (t, J= 7.7 Hz, 1H), 7.16 (d, J= 7.4 Hz, 1H), 6.95 (d, J= 8.2 Hz, 1H), 6.89 (t, J= 7.4 Hz, 1H).13C-NMR (101 MHz, DMSO-d6): d 154.4, 148.7, 147.3, 143.9, 133.4, 130.5, 130.1, 123.2, 123.0, 118.9, 115.7.
With potassium phosphate; at 15℃; for 14.0h;Reflux;
To a mixed solution of compound 27 (0.360 g, 1.00 mmol) in dioxane (20 ml) and H 2 O (5 ml), Pd (PPh 3) 2 Cl 2 (0.110 g, 0.100 mmol),Compound 26 (0.140 g, 1.00 mmol) and K3PO4 (0.660 g, 3.00 mmol) were added at 15 C. The mixed solution was refluxed for 14 hours.Ice water (50 ml) was added to stop the reaction,Extraction operation was performed with EtOAc (50 ml × 3). The obtained organic layer was washed with brine (50 ml), dried over Na 2 SO 4, filtered and concentrated to obtain a crude product.The crude product was purified by a silica gel column to obtain 0.100 g of compound 28 as a pale yellow solid.
2-(4-amino-3-bromo-5-nitropyridin-2-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; ethanol; water; at 85℃;Inert atmosphere; Sealed tube;
A dried RBF was charged with Na2CO3 (61.7 g, 582 mmol), in water (75 mL) and was stirred until a solution was obtained. THF (750 mL) and EtOH (150 mL) were then added and the solution was sparged with argon during the following additions; <strong>[1268521-33-0]3-bromo-2-chloro-5-nitropyridin-4-amine</strong> (49 g, 194 mmol) was charged, and phenylboronic acid (53.5 g, 388 mmol). After 20 min of sparging argon, Pd(PPh3)4 (17.9 g, 15.5 mmol) was charged. The reaction was sealed and was run under argon at 85 C. Once the reaction was deemed complete it was concentrated directly. To the residual was added water, and the mixture extracted with EtOAc. The combined organic fractions were combined, dried with MgSO4 and concentrated. The residual was purified via silica gel column chromatography, eluting with 0-30% EtOAc/Hexane. 2-(4-amino-3-bromo-5-nitropyridin-2-yl)phenol was isolated as a red semi solid (39 g, 65% yield).
With tetrakis(triphenylphosphine) palladium(0); tetrabutyl-ammonium chloride; potassium carbonate; In ethanol; water; toluene; at 78℃; for 10h;Inert atmosphere;
SM1 (50g, 362.50mmol), SM2 (109.07g, 362.50mmol),Tetrakis (triphenylphosphine) palladium(20.95g, 18.16mmol),Potassium carbonate (100.20g, 725.00mmol),Tetrabutylammonium chloride (5.03g, 18.12mmol),Toluene (30mL), ethanol (16mL) and deionized water (8mL) were added to the round-bottom flask. The temperature was raised to 78 C under nitrogen protection and stirred for 10 hours.The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure; the resulting crude product was purified by silica gel column chromatography using n-heptane as the mobile phase.Then recrystallize and purify with dichloromethane / ethyl acetate system to obtain intermediate I-A-1(87.13g, 90% yield).
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In tetrahydrofuran; water; for 12h;Inert atmosphere; Reflux;
<strong>[17823-40-4]4-Bromo-2,3,5,6-tetrafluorobenzonitrile</strong> (5 g, 19.6 mmol), (2-hydroxyphenyl)boronic acid (23.6 mmol), Na2CO3 (59.0 mmol, 2M in aqueous solution) and Pd(PPh)3Cl2 (5 mol %) were dissolved in THF and distilled water (depending on amount of Na2CO3). The solution was refluxed for 12 h under a nitrogen atmosphere and then cooled down to room temperature. The solution was extracted using ethyl acetate and distilled water. The solution of an organic layer was evaporated under vacuum and purified by flash column chromatography using ethyl acetate:hexane (1:4) as an eluent in order to remove starting materials the hydroxy group. The crude reaction mixture was obtained about 3 g. After flash column purification, the crude reaction mixture (3 g, 11.2 mmol) and K2CO3 (22.5 mmol) were dissolved in DMF. The solution was stirred for several hours at 100 Celsius degree under a nitrogen atmosphere and then cooled down to room temperature. The reaction progress checked by TLC. The solution was extracted using ethyl acetate and distilled water. Solvent of the organic layer was evaporated under vacuum and purified by column chromatography using ethyl acetate:hexane (1:4) as an eluent. A white powdery product was obtained (i1, about 1 g). 1H NMR (500 MHz, CDCl3) delta 7.50-7.53 (m, 1H), 7.69-7.70 (m, 2H), 8.13 (d, J=7.5 Hz, 1H). 19F NMR (470 MHz, CDCl3) delta -145.02 (td, JF=51.7, 18.8 Hz, 1F), -136.67 (td, JF=65.8, 42.3 Hz, 1F), -130.61 (td, JF=18.8, 14.1 Hz, 1F), MS (APCI) m/z 247.07 [(M)+].
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 90℃; for 16h; Inert atmosphere;
General procedure for Suzuki coupling (GP4) for compounds24a-b, 29a-b, 35a-l
General procedure: Under argon atmosphere the appropriate arylhalide 1 (eq.) was dissolved inwater and 1,4-dioxane (1:1). Sodiumcarbonate (3 eq.), the corresponding boronic acid (1.2 eq.) andtetrakis (triphenylphosphine) palladium (0.1 eq.) were added. Thereaction mixture was heated to 90 C for 16 h. After full conversion(LCMS control) the mixture was cooled to room temperature andEtOAc and sat. aqueous NaHCO3 solution were added. The mixturewas extracted with EtOAc (3x), the combined organic layers weredried over sodium sulfate and concentrated under reduced pressureto obtain the crude. The purification was done using automatedflash chromatography (cyclohexane/EtOAc 1:0 / 0:1).
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